The present invention relates to a series of new oligopeptides, which have renin-inhibitory and, hence, hypotensive activities, and which are thus of particular value in the treatment of hypertension induced by failures in the renin-angiotensin system of the mammalian, especially human body. The invention also relates to the preparation of such compounds and to their use in such treatment. The oligopeptides of the present invention include in their peptide chain a unit derived from the amino acid commonly known as cyclostatine, whose formal name is (3S, 4S)-4-amino-5-cyclohexyl-3-hydroxypentanoic acid and which is also sometimes referred to as "ACHPA".
There is considerable evidence that reduction of elevated blood pressure reduces the risks of morbidity and mortality. Elevated blood pressure (hypertension) can be caused by a variety of factors and a large number of drugs is available for the treatment of hypertension, the drug of choice being dictated in large measure by the cause of the hypertension.
Some of the factors known to play a role in the onset of hypertension in the mammalian body is an oligopeptide known as angiotensin II. Angiotensin I is a polypeptide formed by the action of renin upon a plasma protein, and this is converted to angiotensin II by the action of ACE (angiotensin converting enzyme). Angiotensin II causes constriction of the arterioles and can produce hypertension. Hypertension of this type can be reduced by reducing the plasma concentration of angiotensin I or II, which, in turn, can be achieved by inhibiting the activity of renin. The number of available drugs having this type of inhibitory activity is very limited, and, to date, no such drug is commercially available.
A variety of peptide derivatives having this type of activity is known. Those prior art compounds believed to be closest to the compounds of the present invention, in that they are based upon the rather uncommon amino acid statine and analogs thereof, are disclosed in European Patent Publications No. 155 809 and No. 184 855 and in copending U.S. patent application Ser. No. 802 038, filed Nov. 26, 1985, now abandoned. Various other prior art discloses other polypeptides having renin-inhibitory activities, but which have some other amino acid unit in place of the cyclostatine unit, which is one of the critical features of the compounds of the present invention, for example U.S. Pat. No. 4 698 329 and U.S. patent application Ser. No. 936 087, filed Nov. 28, 1986, now abandoned.
We have now discovered a series of peptide derivatives having a very marked ability to inhibit the activity of renin, which ability is believed to be significantly better than that of the prior art compounds.
Certain of the compounds of the invention resemble certain of those disclosed in European Patent Publication No. 155 809, although this European Patent Publication also discloses many other compounds which are not relevant to the present invention. However, the compounds of the present invention differ from those of European Patent Publication No. 155 809 primarily in the nature of the groups at the nitrogen terminal end and at the carboxy terminal end of the oligopeptide chain. The compounds of the present invention differ from those of European Patent Publication No. 184 855 primarily in the nature of the groups at the nitrogen terminal end of the oligopeptide chain. The compounds of the present invention differ from those of U.S. patent application Ser. No. 802 038 primarily in the nature of the group at the nitrogen terminal end and also to some extent in the nature of the group at the carboxy terminal end of the oligopeptide chain. The compounds of the present invention differ from those of U.S. patent application Ser. No. 936 087 in the nature of other units in the polypeptide chain.
The compounds of the present invention have, in general, a higher inhibitory activity against renin, much improved absorption when administered by the oral route, lower toxicity, better and stronger enzyme specificity and better water solubility than the compounds of the prior art. These advantages suggest that the compounds of the present invention will be of outstanding value in the treatment of disorders in the mammalian body arising from an imbalances in the level of renin in the blood. In particular, it is well known that the oral route is the preferred route of administration, particularly where (as with the drugs with which the present invention is concerned) drugs are intended for self-administration by the patient, generally over a long period of time. However, a serious disadvantage common to almost all of the known renin-inhibitory oligopeptides, including most of those mentioned in the previous paragraph, is that, in practice, it is necessary to administer them by parenteral routes, e.g. by injection, as suppositories or even by inhalation. This applies even in those cases where the compounds have been suggested for oral use, except for those of U.S. patent application Ser. No. 936 087, since it has subsequently been found that they either are insufficiently stable to enzymes, e.g. esterases, present in the digestive system or are inadequately absorbed from the stomach and/or intestines or both. Of course, the poor stability is expected with oligopeptides, as the mammalian digestive system is specifically designed to break down compounds of that type. Consequently, even if the compounds can be administered orally, such high doses are necessary in order to make up for poor absorption and/or losses caused by digestion as to make oral administration impractical.